Indomethacin Amides As a Novel Molecular Scaffold for Targeting Trypanosoma Cruzi Sterol 14alpha-demethylase

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2009 Apr 10

PMID 19354253

Citations 19

Authors

Mary E Konkle

Tatiana Y Hargrove

Yuliya Y Kleshchenko

Jens P von Kries

Whitney Ridenour

Md Jashim Uddin

Richard M Caprioli

Lawrence J Marnett

W David Nes

Fernando Villalta

Michael R Waterman

Galina I Lepesheva

Affiliations

Soon will be listed here.

Abstract

Trypanosoma cruzi (TC) causes Chagas disease, which in its chronic stage remains incurable. We have shown recently that specific inhibition of TC sterol 14alpha-demethylase (TCCYP51) with imidazole derivatives is effective in killing both extracellular and intracellular human stages of TC. An alternative set of TCCYP51 inhibitors has been identified using optical high throughput screening followed by web-database search for similar structures. The best TCCYP51 inhibitor from this search was found to have structural similarity to a class of cyclooxygenase-2-selective inhibitors, the indomethacin-amides. A number of indomethacin-amides were found to bind to TCCYP51, inhibit its activity in vitro, and produce strong antiparasitic effects in the cultured TC cells. Analysis of TC sterol composition indicated that the mode of action of the compounds is by inhibition of sterol biosynthesis in the parasite.

Citing Articles

Computational approaches for drug discovery against trypanosomatid-caused diseases.

Pereira C, Saye M, Reigada C, Silber A, Labadie G, Miranda M Parasitology. 2020; 147(6):611-633.

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CYP51 as drug targets for fungi and protozoan parasites: past, present and future.

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